UA81910C2 - Topical pharmaceutical preparation - Google Patents

Abstract

A topical pharmaceutical preparation for administering slightly soluble PDE4 inhibitor is described. A surprisingly good systemic bioavailability is observed with this dosage form. The invention relates to the pharmaceutical technology, in particular the topical pharmaceutical preparation containing as an active ingredient one of the following substances: Roflumilast, the salts of Roflumilast, N-oxide of the pyridine residue of Roflumilast or its salts. The pharmaceutical preparation also contains one or several carriers and /or excipients acceptable for the topical use. One of the excipients represents polyethylene glycol.

Description

Description of the invention

This invention relates to the field of pharmaceutical technology and, in particular, to a pharmaceutical preparation for local application 2, which contains as an active ingredient a sparingly soluble ROE inhibitor 4. The invention also relates to a method of obtaining such a pharmaceutical preparation for local application and its use for the treatment of skin and eye diseases, as well as respiratory tract diseases.

Cyclonucleotide phosphodiesterase (POE) inhibitors (primarily type 4) are currently of particular interest as a new generation of active substances suitable for the treatment of inflammatory diseases, primarily airway inflammation 70 , including asthma or airway obstruction (eg, chronic obstructive pulmonary disease (COPD)). . There are now a large number of ROE4 inhibitors, including an oral dosage form that contains as an active ingredient

IM-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (INN SMNN - international non-proprietary name) roflumilast) are undergoing intensive clinical trials. This and other compounds with a 12 benzamide structure and their use as cyclonucleotide phosphodiesterase (POE) inhibitors are described in (MUO 95/013381. In (M/O 95/01338) similar active substances were also proposed to be used for the treatment of certain skin diseases (for example In (MO 00/53182| it was proposed to use roflumilast or its M-oxide for the treatment of multiple sclerosis.

For the treatment of skin diseases, it is advisable to use the pharmaceutical active substance as part of a pharmaceutical preparation suitable for local use. However, experts in this field are well aware that finding dosage forms for local use that would ensure effective entry into the body of an active substance that has an exceptionally low solubility can be a difficult or even impossible task. So, in particular, the water solubility of the ROE 4 inhibitor was established

IM-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (INN roflumilast), which is described in IMO 95/01338), is only 0.53 mg/l at 2126 g)

In accordance with the invention, it was unexpectedly found that pharmaceutical preparations for local use, which contain the ROE 4 inhibitor roflumilast, which has a low solubility, show a rather high efficiency in the treatment of dermatoses when they are applied locally. In addition, it was unexpectedly established that, in addition to the local effect, similar pharmaceutical preparations also have an exceptionally high systemic effect, comparable to the effect that is characteristic of dosage forms intended for oral "-- use.

According to this, the first object of the present invention is a pharmaceutical preparation that would allow the possibility of its local application and that contains a pharmaceutical active substance together with one or more pharmaceutical carriers and/or excipients suitable for local

For use, this pharmaceutical active substance is a compound selected from the group that includes roflumilast, salts of roflumilast, M-oxide of roflumilast and its salts.

Roflumilast is the international non-proprietary name of the compound of the formula "

NO 2 - NN 2» I

MF, so 2 Z - (se) o - in which

K1 means a difluoromethoxy group,

So K2 means cyclopropylmethoxy group and

KZ stands for 3,5-dichloropyrid-4-yl.

The chemical name of this compound sounds like

IM-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (INN roflumilast). Chemical name

HF) of roflumilast M-oxide sounds like 3-cyclopropylmethoxy-4-difluoromethoxy-M-(3,5-dichloropyrid-4-yl-1-oxide)benzamide.

Such a compound of formula I!, its salts, its M-oxide and its salts, as well as the use of these compounds as inhibitors of phosphodiesterase type 4 (POE4) are described in the application (MO 95/01338).

Salts that can form compounds of formula I include, depending on their substitution scheme, all possible acid addition salts, but above all all possible salts with bases. In particular, pharmacologically acceptable salts with inorganic and organic acids and bases, which are usually used in pharmaceutical technology, can be noted. Pharmacologically unacceptable salts, which can be formed, for example, as primary products in the production of the above-mentioned compounds on an industrial scale, are translated or converted into their pharmacologically acceptable salts by known methods. Suitable pharmacologically acceptable salts include, firstly, water-soluble and water-insoluble acid addition salts formed, for example, with such acids as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, SO -gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid, wherein the acids are used for salt formation in equimolar amounts or in amounts that differ from these, depending on whether the acid is monobasic or polybasic, and depending on from the specific type of salt to be obtained.

The corresponding pharmacologically acceptable salts, secondly, also include salts formed with bases, which are the most preferred. Examples of such basic salts include lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, while such bases are also used for salt formation in equimolar amounts or in amounts that differ from them.

The relative content of the pharmaceutical active substance in the pharmaceutical preparation proposed in the invention (in percent by mass in terms of the mass of the final pharmaceutical preparation, wt. 90) is usually from 0.001 to BO mass. 9Uo. In the preferred version, the relative content of the pharmaceutical active substance is up to 1 Imas.9ov.

Pharmaceutical carriers and/or auxiliary substances that can be included in the composition of dosage forms for local use according to the invention mainly include traditional carriers and/or auxiliary substances known to specialists in this field for their use in pharmaceutical preparations for external (dermal) use (dermatological drugs). Examples of this include carriers and/or auxiliary substances that are suitable for the preparation of powders (powders), emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels, foams or solutions, as well as transdermal therapeutic system

The pharmaceutical preparation proposed in the invention for local use can be obtained by methods well known to specialists in this field. (8)

Traditional dermatological medicinal products and methods of their preparation, as well as preferred carriers and/or excipients for individual pharmaceutical preparations are described, for example, in the book "Rpaptageciivspe Tesppoiodie" (ZyskKeg, Hyspv, Zreizeg, ed. Seogud Tpiete Megiad, 1978, p .629 and further)). In the first embodiment of the invention, the pharmaceutical preparation for local use proposed in it is presented in the form of a semi-solid or soft dosage form. Examples of such medicinal forms are, in particular, ointments (for example, ointment-solution, suspension ointment), creams, gels or pastes. b

Emulsions of the type "oil in water" or "water in oil" are usually called creams. Fatty alcohols, such as lauryl, cetyl or stearyl alcohol, are mainly used as the oil phase in them, while fatty

335 Acids, such as palmitic or stearic acid, liquid or solid paraffins or ozokerite, liquid to solid waxes, such as isopropyl myristate, natural or semi-synthetic fat, such as coconut fatty acid triglycerides, solid oils, such as hydrogenated peanut or castor oil, or unsaturated esters of glycerol and fatty acids, such as glycerol monostearate or glycerol distearate. Acceptable emulsifiers include surface-active substances, such as non-inogenic "

Surfactants, in particular esters of polyhydric alcohols and fatty acids or their ethylene oxide adducts, such as esters of polyglycerol and fatty acids or esters of polyoxyethylene sorbitan and fatty acids (TzhsheepF), ISI firm), esters of sorbitan and fatty acids (ZrapF, firm ICI), such as, for example, sorbitanoleate and/or sorbitan isostearate, sterols, as well as polyoxyethylene and fatty alcohol esters or polyoxyethylene and fatty acid esters, or anionic surfactants, in particular alkali metal sulfates of fatty alcohols, for example, sodium lauryl sulfate, cetyl sulfate sodium or sodium stearyl sulfate, which are usually used in the presence of specified fatty alcohols, for example cetyl alcohol or stearyl alcohol.

Among other things, substances that prevent the drying of the cream can be added to the aqueous phase, for example, polyhydric alcohols, such as glycerin, sorbitol, propylene glycol and/or polyethylene glycols, as well as preservatives, fragrances (perfumes) and other additives.

Ointments can be anhydrous and contain as a basis paraffins, which are suitable for local use and are - liquid (melt) at body temperature and which primarily include low-viscosity paraffin, as well as the above-mentioned natural or semi-synthetic fats, for example, triglycerides of fatty acids of coconut nut, hardened oils, such as hydrogenated peanut or castor oil, unsaturated esters of glycerol and fatty acids, such as glycerol monostearate and distearate, silicones, such as polydimethylsiloxanes, particularly in Hexamethyldisiloxane or octamethyltrisiloxane, and, for example, the fatty alcohols mentioned above for water-based creams based and which increase the water absorption capacity, sterols, wool waxes, other emulsifiers and/or other additives.

GF) Gels are divided into aqueous gels, anhydrous gels, and gels with a low water content, and they consist of a gelling material that swells. Transparent hydrogels based on inorganic or organic macromolecules are of particular interest. Macromolecular inorganic components with gel-forming properties mainly include water or water-absorbing (hygroscopic) silicates, such as aluminosilicates, for example bentonite, magnesium aluminosilicates, for example MeeditF of the Mapaegrii Ehr company. Sogr., or colloidal silica, for example Aegozikzh of the YuOedivzza company. For example, natural, semi-synthetic or synthetic polymers are used as macromolecular organic substances. Natural and semi-synthetic polymers are derivatives, for example, of polysaccharides with different carbohydrate chains, such as cellulose, 65 Starch, tragacanth, gum arabic, agar, gelatin, alginic acid and its salts, for example, sodium alginate and its derivatives, (lower) alkyl cellulose , for example methyl or ethyl cellulose, carboxy or hydroxy-(lower) alkyl cellulose, for example carboxymethyl or hydroxypropyl cellulose. Synthetic gel-forming polymers are unsaturated substituted aliphatic compounds such as vinyl alcohol, vinyl pyrrolidone, acrylic or methacrylic acid. As an example of such polymers, we can name derivatives of polyvinyl alcohol, such as Roiumio!? UmUaskKeg company, polyvinylpyrrolidone, such as KoiPdop"E company VAZE or

RoiuriazaopO company Sepegai! Apiipe, polyacrylates and polymethacrylates, such as Kopadii 5F of the company Kopt apa Nagzv.

The composition of gels can include traditional additives, such as preservatives or aromatic substances (perfumes).

Pastes are creams or ointments, which include the components mentioned above, as well as powdered components that absorb the secretion, such as metal oxides, such as titanium oxide or zinc oxide, as well as talc and/or aluminosilicates, which are ground to a powder state. the purpose of which is to bind moisture or secretion.

In one of the preferred embodiments of the invention, the pharmaceutical preparation for local use proposed in it is a semi-solid pharmaceutical preparation that contains polyethylene glycol as one of the excipients, in particular polyethylene glycol 400.

In another embodiment of the invention, the pharmaceutical preparation for local use proposed therein is presented in the form of a transdermal therapeutic system (TS), for example, in the form of a system described in |

Mepadzdezeiizsnai trН, 5ishnoagi 1997, p. 81 et seq.). The main characteristic features of TTS are the entry into the skin of a strictly defined amount of the medicinal substance, the total dose of the medicinal substance contained in them, the total area of the skin area covered by them, and the area of the area, which may be different from that on which the medicinal substance is released into the skin , the presence of a covering layer (base) impermeable to the medicinal substance, the presence of a reservoir with the medicinal substance, the presence of an element that controls or regulates the entry of the medicinal substance into the skin, the presence of a sticky layer (a layer of glue that is activated by short-term pressure) and the presence of a protective layer, which is deleted. In some cases, the same element can perform more than one function at the same time, for example, a suitable adhesive matrix can perform the function of a reservoir with a medicinal substance, an element that controls or regulates the entry of a medicinal substance into the skin, and an adhesive layer. From the point of view of pharmaceutical technology, TCs are classified into different types depending on the features of their implementation of the function that controls or regulates the release of the medicinal substance, that is, depending on the method by which the entry of the medicinal substance into the skin is controlled or regulated. As an example, we can cite TTS with controlled release of a medicinal substance due to penetration through a membrane (membrane-regulated drug delivery system), TTS with controlled release of a medicinal substance due to diffusion through the matrix, and TT with controlled release using microreservoirs medicinal substance.

TTS with controlled release of the medicinal substance due to penetration through the membrane are distinguished by the presence of a polymer membrane made of a copolymer of polyvinyl acetate and vinyl acetate (Spgopoteg F), which regulates the penetration of the medicinal substance from the reservoir into the skin. The medicinal substance is initially contained in the reservoir in the form of solid particles or in the form of a dispersion or solution. The polymer membrane can be connected to the tank by various methods (extrusion, encapsulation, microencapsulation). TCs with controlled release of the medicinal substance due to diffusion through the matrix have a comparatively simpler structure. In TTS of this type, there is no separate element that regulates the entry of medicinal substances into the skin. Instead, the release of the medicinal substance is regulated by a lipophilic or hydrophilic polymer matrix and/or a sticky layer. Depending on the properties of the TTS matrix of this type, it can be divided into TTS with a gel-like matrix and TTS, which are solid polymer laminates. the substance in such TTS is formed by the matrix due to the dissolution of the medicinal substance in it (monolithic system) or due to the homogeneous dispersion of solid particles of the medicinal substance in it. The matrix-type TS can be made by mixing the particles of the medicinal substance with a viscous liquid or a semi-solid polymer at room temperature with subsequent cross-linking of polymer chains. Another possibility is mixing the medicinal substance at an elevated temperature with a softened polymer (hot melt mixing method) or mixing two components (dissolved in an organic solvent) with the subsequent removal of the solvent in a vacuum (by evaporation of the solvent). For forming, the obtained mass can be poured into appropriate forms, distributed in an even layer with the help of special devices (squeegees) or extruded. In TS with controlled release of the medicinal substance with the help of microreservoirs (system of delivery of microencapsulated medicinal substance,

MOO-principle from English "tisgozeaied ahod aeiiimegu") a set of cells or compartments that contain the active substance, in Microscopic sizes from 10 to 200 μm, are immersed in a matrix that simultaneously performs the function of a reservoir with a medicinal substance and an element that regulates its entry into the skin. Due to the presence of (Ф) matrices, similar TTSs actually belong to matrix-type systems. For the production of such systems, the medicinal substance is first dispersed together with water and 4095 polyethylene glycol 400 in isopropyl palmitate, which performs the function of a substance that promotes penetration. The resulting dispersion is immersed in a viscous silicone elastomer, which is simultaneously subjected to catalytic polymerization, using a special technology of high-intensity dispersion.

It is possible, in particular, to give the necessary shape to the matrix containing the medicinal substance by converting it into a molten state or by extrusion, after which it can be connected to the carrier element by the above-described method. Depending on the physico-chemical properties of medicinal substances and the required profile of their release, the matrix can be covered with a layer of biocompatible polymer, changing with its help the mechanism and rate of release of the medicinal substance.

In another variant of the implementation of the invention, the pharmaceutical preparation for local use proposed in it is presented in the form of a dosage form for the eyes (ophthalmic drugs). Examples of similar dosage forms of this type include eye wash solutions (eye baths) or eye lotions, eye films, eye ointments, eye sprays, eye drops, intraocular injections, and eye ointments. for ever. In a preferred version, the dosage form proposed in the invention is an eye ointment or eye drops. Eye drops according to the invention are preferably water or oil suspensions of the active substance. In this regard, it is preferable that the size 9090 of all particles of the active substance used is less than 1 Ohm.

In the composition of aqueous suspensions as their stabilizers, in addition to preservatives (for example, chlorocresol, compounds of 7/0 phenylmercury, phenylethanol, benzalkonium chloride or mixtures of individual components), as well as in addition to the sodium chloride used under certain conditions to provide isotonicity, it is preferable to use, for example, substituted cellulose ( for example methylcellulose, hydroxypropylmethylcellulose), polyvinyl alcohol, polyvinylpyrrolidone. In the case of oil-based eye drops per se according to the invention, it is preferable to use castor oil, peanut oil or medium chain triglycerides. For 7/5 preparation of eye ointments according to the invention, you can use ointment bases that have the following properties: sterility or an exceptionally low content of microorganisms, lack of an irritating effect, good activity, ensuring homogeneous distribution of the active substance or its solution in the volume of the ointment, susceptibility ( softness), the ability to quickly spread in the form of a thin film on the surface of the eyeball, good adhesion to the surface of the eyeball, good stability and minimal deterioration of visual acuity. Taking this into account, it is preferable to use hydrocarbon- or cholesterol-containing ointment bases for the preparation of eye ointments according to the invention. When using petroleum jelly, it is preferable to add liquid paraffin to it to reduce its viscosity. For effective and uniform distribution of the drug on the surface of the eyeball according to the invention, it is preferable to prepare compositions of limited viscosity. So, in particular, the viscosity of the drug at 3222; should preferably be less than 100O0mPa.s, and its yield strength should preferably be less than 25 Zb0OmPa. In suspension ointments, the size of the 9095 particles of the active substance according to the invention should preferably be less than 1 µm, and there should not be particles larger than 9 µm. In accordance with the invention, preservatives such as benzalkonium chloride, thiomersal or phenylethyl alcohol are preferably included in the composition of ointments-emulsions of type i) "water in oil" according to the invention.

Examples o 30 Obtaining the dosage forms proposed in the invention

Example 1 h-

Composition per 550 grams: Polyethylene glycol 400 AlO, 35 Sagroro!y 9349 8.25g soroflumilast 1.375g sodium hydroxide solution 4.5. purified water in an amount that is not enough up to 550.00 g "

To prepare the dosage form, the active substance is dissolved in the specified amount of polyethylene glycol at a temperature of the order of 60-702C. Next, approximately 90 grams of purified water is added and mixed until homogenous, after which the Sagroro is dispersed in this mixture with the help of a high-speed mixer until homogenous! 9349. Then, with slow stirring, a solution of sodium hydroxide is added until the pH value is 6.5-7.5. Next, add the remaining amount of water, which is not enough for the final mass, and mix until homogeneity.

Example 2 c Composition based on 550 grams: shk roflumilast 1.65 g polyethylene glycol 400 440.00 g o polyethylene glycol 4000 in the amount that is not enough for 550.0 g - 50

To prepare the dosage form, both polyethylene glycols are heated to 702 to obtain a transparent melt. Next, the active substance is added, also obtaining a transparent solution. The drug is cooled to room temperature with slow stirring.

Example C 59 Composition based on 550 grams: o roflumilast 11 g ko Tedo Sage 1509 27.50 g (TA. Soidazsptid) neutral oil (Midius! 8129) 1137.50 g 60 polyethylene glycol 400 275.00 g cetostearyl alcohol 11, purified water in the amount , which is not enough to 550g

To prepare the dosage form, first of all, a clear solution of neutral oil, because of cetostearyl alcohol and Tedo Sage 15059 is obtained at a temperature of approximately 702C. Polyethylene glycol with roflumilast dissolved in it is then mixed into this solution using a high-speed stirrer. Water heated to 7090 is added to the lipid phase. After that, the mixture is homogenized using a homogenizer

Titakh At the end, the drug is stirred until cooling (to room temperature).

Example 4

Composition per 100 grams: roflumilast 0.25g neutral oil (Midiuso! 81295) 16.00g glycerin monostearate 8.00g

Sgetorpog AbYa (VAZE company) /-4.00g polyethylene glycol 400 62.50g purified water in an amount that is not enough for 100.00g

To prepare the dosage form, all components (except water) are heated together to a temperature of about 70-80 to obtain a transparent solution. After that, water is added while stirring, and the drug obtained in this way is cooled while stirring to room temperature.

Example 5

Composition per 100 grams: roflumilast 0.25 g liquid paraffin 15.00 g wool wax 5.00 g white vaseline in an amount that is not enough for 100 g

For the preparation of the medicinal form, a transparent melt of liquid paraffin, wool wax and Ge) of white vaseline is obtained at a temperature of about 80 2С. Then micronized active substance is added and the preparation is stirred until cooling to room temperature.

Example 6 o roflumilast О10 g h: liquid paraffin 10.00 g wool wax 5.00 g (22 white vaseline in an amount that is not enough for 100 g чe 3 o The medicinal form of the specified composition is obtained similarly to example 5. (ge)

Example 7 roflumilast Oog "neutral oil (Midiuso! 81295) 16.00 g glycerol monostearate 8.00 g - s Stetorpog AbF (VAZE company) / 2.00 g h " polyethylene glycol. 400 62.50g "purified water in an amount that is not enough for 100.00g

The pharmaceutical form of the specified composition is obtained similarly to example 4. (ee) Example 8 - roflumilast Oog (Se) neutral oil (Midiuo! 81295) 16.00g glycerin monostearate 8.00g - Sgetorpog AbYa (VAZE company) /-4.00g 2 polyethylene glycol 400 62.50g purified water 100.00g

The medicinal form of the specified composition is obtained similarly to example 4.

Example 9 (F) Eye ointment composition (amount per 1000 grams): le ! roflumilast 1g in cetyl alcohol Ag highly viscous paraffin 200g white petroleum jelly 795g

Preparation: First, a transparent melt of cetyl alcohol, 65% high-viscosity paraffin and white petroleum jelly is obtained at a temperature of about 70 °C. After that, micronized roflumilast (with a size of 9090 particles less than 1µm) is mixed in and a homogeneous dispersion is prepared using a homogenizer of the OKha-Tigtakh type. The suspension is cooled with stirring to room temperature and packaged in appropriate tubes.

Example 10

The composition of the eye solution in the form of an emulsion (amount per 1000 milliliters): roflumilast 1.5g medium-chain triglycerides 100.0g lecithin 12.0g glycerol 25.0g 70 thiomersal b 1g purified water in an amount that is not enough for 1000ml

Preparation: First, at a temperature of 30-402C, roflumilast is dissolved in triglycerides with an average chain length and glycerol, and then lecithin. After that, with intensive stirring, purified water is added and then homogenized until the size of the droplets of the dispersed phase becomes less than 50 nm. Further, with stirring, thiomersal is dissolved. The resulting emulsion is filtered through a filter with a pore size of 0.45 μm and packaged in appropriate containers.

Example 11

The composition of the nasal ointment (quantity per 1000 grams): roflumilast 1g cetyl alcohol Ag wool wax BOG high-viscosity paraffin 200g white petroleum jelly 74A5g cm o

Preparation: First, a transparent melt of cetyl alcohol, high-viscosity paraffin, wool wax and white petroleum jelly is obtained at a temperature of about 70 °C. Next, micronized roflumilast (with a size of 9095 particles less than 1μm) is mixed in and a homogeneous dispersion is prepared using an OKha-Titah type homogenizer. The suspension is cooled with stirring to room temperature and packaged in appropriate tubes. h-

Study of pharmacokinetic properties of pharmaceutical preparations for local use

Comparison of the pharmacokinetic parameters of the pharmaceutical preparations proposed in the invention for b local use with the dosage form for oral use h-

Example A

The preparation from example 7 and the preparation from example 8, which contain | "Si|-roflumilast. The concentration of the radioactive isotope was determined in the plasma after 1 hour, 4 hours, 8 hours, 24 hours and in the urine (0-24 hours) (item 5). The active substance was administered in a dose of 1.7 mg/kg in all cases.

Results: « preparation from example 7: Stakh: 0.214 mg eq./l, LUOS (0-24h): 4.13 (mg eq./l-h), with c preparation from example 8: Stakh: 0.214 mg eq. /l, LUOS (0-24h): 3.99 (mg eq./l-h).

Results normalized to mg/kg: "from" preparation from example 7: Stach: 0.126, AOS: 2.43,

Preparation from example 8: Stach: 0.126, AC: 2.35.

Comparison with kinetic indicators after oral administration of the active substance in a dose of mg/kg: oo Stach: 0.225 mg eqUl, AOS (0-24h): 3.10 (mg eq./l-h).

The ratio of the AC indicator (for the drug from example 7) to the AOS indicator (for the dosage form for oral use) is 7896, and the ratio of the AOS indicator (for the drug from example 8) to the A!McS indicator (for dosage form for oral use) is 7690.

The results of the comparison of the excretion of the active substance with urine: -th preparation from example 7: 19.495 per dose, o preparation from example 8: 18.095 per dose, dosage form for oral use: 18.495 per dose.

Conclusions

After percutaneous administration to rats | "C|-roflumilast at a dose of 1.7 mg/kg, all the active substance labeled with a radioactive isotope penetrates the skin quite well, and its concentration in the plasma reaches the maximum level, which (F) is equal to 0.214 mg equiv./l, after 4 hours, regardless of the composition In terms of the entire active substance labeled with a radioactive isotope, the AOS-indicators and indicators of excretion of the active substance with urine after its transdermal administration differ only slightly from the same indicators obtained after oral administration of the active substance.

Example B

On a shaved area of skin of rats (male UMiviag rats) with an area of 4 cm2? applied the drug from example 5, which contains | "SI-roflumilast. The concentration of the radioactive isotope was determined in the plasma after 1 hour, 4 hours, 8 hours, 24 hours and in the urine (0-24 hours) (item 5). The active substance was administered in a dose of 1.77 mg/kg in all cases. 65 Results : preparation from example 5: Stach: 0.331 mg eqUl, AOS (0-24h): 4.99 (mg eq./l-h).

Results normalized to mg/kg: preparation from example 5: Stach: 0.187, AOS: 2.82.

Comparison with kinetic indicators after oral administration of the active substance in a dose of mg/kg:

Stach: 0.225 mg eq./l, AOS (0-24h): 3.10 (mg eq./l-h).

The results of the comparison of the excretion of the active substance with urine: the drug from example 5: 22.095 per dose, the dosage form for oral use: 18.495 per dose.

Conclusions 70 The above data indicate that roflumilast is absorbed from the preparation indicated in Example 5 even slightly better than from the preparation indicated in Example 7 or Example 8. Within 24 hours after the introduction of the active substance, 2295 of its total amount is excreted in the urine, which also does not differ much from the amount of the active substance that is excreted in the urine after dermal application of the drug from example 7 or 8. Comparison with the dosage form for oral use indicates that that /5 Regardless of the composition of the drug for local use, the indicators of Stach and AC, as well as the indicators of excretion of the active substance with urine, have similar values.

The dosage forms proposed in the invention can be used for the treatment and prevention of all those diseases in which the use of ROEA4 inhibitors is indicated. Selective cyclonucleotide phosphodiesterase (POE) inhibitors (primarily type 4) are, first, suitable for use as bronchial therapeutics (for the treatment of airway obstruction because they have a dilating effect and also have the ability to increase the respiratory rate and stimulate breathing) and to eliminate erectile dysfunction, as they have a vasodilator effect, and, secondly, they are primarily suitable for the treatment of diseases, mainly of an inflammatory nature, mediated by such mediators as histamine, RAE factor (platelet activation factor), arachidonic acid derivatives, in particular with leukotrienes and prostaglandins, cytokines, interleukins, chemokines, o-, p- and y-interferon, tumor necrosis factor (TME-factor) or free oxygen radicals, as well as proteases, for example, diseases of the respiratory tract (for and) prevention of asthma), skin , central nervous system, intestines, eyes and joints. In accordance with this, the pharmaceutical preparations proposed in the invention can be used in medicine and veterinary medicine, for example, for the treatment and prevention of the following diseases: acute and chronic (primarily inflammatory suso caused by allergens) diseases of the respiratory tract of various etiologies (bronchitis, allergic bronchitis, bronchial asthma, COPD ), dermatoses (primarily proliferative, inflammatory, and allergic in nature), such as, for example, psoriasis (scaly lichen planus), toxic and allergic contact eczema, atopic dermatitis, b seborrheic eczema, lichen planus, solar erythema, itching in the genital area and anus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and large pyodermas, endogenous and exogenous acne, pink acne and other proliferative, inflammatory and allergic skin diseases, diseases based on excess release of the TME factor and leukotrienes, for example, diseases of the arthritic type (rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions), diseases of the immune system (AIDS, multiple sclerosis), various types of shock, septic shock, endotoxin bacterial-toxic shock, gram-negative sepsis, toxic shock syndrome and RDSD (respiratory distress syndrome adults)| and diffuse inflammations in the gastrointestinal tract (Crohn's disease and ulcerative colitis), diseases based on allergic and/or chronic abnormal immunological reactions and in the upper respiratory tract (in the pharyngeal area, nasal area) and adjacent areas (in the "" area of the paranasal sinuses, the area of the eyes) and examples of which can be named allergic rhinitis/sinusitis, chronic rhinitis/sinusitis, allergic conjunctivitis, conjunctivitis caused by bacteria, viruses or fungi, inflammatory conditions after intraocular lens implantation , inflammation of the optic nerve (optic neuritis), keratitis,

Go! dry eye syndrome (dry keratitis), uveitis, glaucoma, retinal edema, retinitis pigmentosa, diabetic retinopathy and nasal polyps, as well as heart diseases for the treatment of which ROE inhibitors can be used and - as an example of which we can name heart failure, or diseases , for the treatment of which ROE inhibitors can be used due to their relaxing effect on the tissue and as an example of which we can name 50r erectile dysfunction or renal and ureteral colic associated with renal calculi, or CNS diseases, such as, for example, such as depression or arteriosclerotic dementia. oz The pharmaceutical preparations proposed in the invention are most suitable for the treatment of skin diseases, in particular dermatoses (primarily proliferative, inflammatory and allergic in nature), such as, for example, psoriasis (scaly lichen planus), toxic and allergic contact eczema, atopic dermatitis, seborrheic eczema, lichen planus , solar erythema, itching in the genital area and anus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and large pyodermas, endogenous and exogenous acne, (F) pink acne and other proliferative, inflammatory and allergic skin diseases. The pharmaceutical preparations proposed in the invention are preferably used for the treatment of psoriasis and atopic dermatitis.

According to this, the invention also relates to the use of roflumilast, roflumilast salts, M-oxide of roflumilast or its salts for the preparation of a pharmaceutical preparation for local cutaneous use, intended for the treatment of skin diseases, in which the use of ROE 4 inhibitors is indicated.

Such a pharmaceutical preparation is preferably used for the treatment of dermatoses (primarily proliferative, inflammatory and allergic in nature), such as, for example, psoriasis (scaly lichen planus), toxic and allergic contact eczema, atopic dermatitis, seborrheic eczema, lichen planus, solar b5 erythema, itching in genital area and anus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and large pyodermas, endogenous and exogenous acne, pink acne and other proliferative, inflammatory and allergic skin diseases.

The present invention further relates to a method of treating mammals, including humans, suffering from one of the above diseases. This method is characterized by the fact that a therapeutically effective and pharmacologically acceptable amount of a pharmaceutical active substance selected from the group of compounds that includes roflumilast, salts of roflumilast,

M-oxide of roflumilast and its salts, and which is introduced into the body as part of the pharmaceutical preparation proposed in the invention for local use. Diseases for the treatment of which it is preferable to use the method proposed in the invention are skin diseases, in particular dermatoses (primarily 7/0 of a proliferative, inflammatory and allergic nature), such as, for example, psoriasis (scaly lichen planus), toxic and allergic contact eczema, atopic dermatitis ) . The method proposed in the invention differs in that the introduction of the active /5 Beetroot into the body consists in its dermal application, that is, in applying the pharmaceutical preparations proposed in the invention for local application to the skin or mucous membranes.

In another preferred embodiment, the invention provides a method of treating mammals, including humans, suffering from an eye disease in which the use of POE4 inhibitors is indicated. Such an eye disease is preferably selected from the group that includes allergic conjunctivitis, conjunctivitis caused by bacteria, viruses or fungi, inflammatory conditions after intraocular lens implantation, inflammation of the optic nerve (optic neuritis), keratitis, dry eye syndrome ( dry keratitis), uveitis, glaucoma, retinal edema, retinitis pigmentosa and diabetic retinopathy. An eye disease, for the treatment of which it is preferable to use the method proposed in the invention, is allergic conjunctivitis, conjunctivitis caused by bacteria, viruses or fungi, inflammatory conditions after intraocular implantation of lenses or uveitis. The method proposed in the invention differs in that the introduction of the active substance into the body consists in treating the eye with the drug proposed in the invention.

The good systemic availability, which is unexpectedly observed with the local application of the pharmaceutical preparations proposed in the invention, allows you to additionally use them for systemic treatment and thus for the treatment of all other diseases in which the use of ROE 4 inhibitors is indicated, primarily the above-mentioned diseases. According to this, the invention also relates to the use of roflumilast, salts of roflumilast, M-oxide of roflumilast or its salts for the preparation of a pharmaceutical preparation for local cutaneous application, intended for the systemic treatment of diseases in which the use of inhibitors b

ROE 4. Such diseases mainly include acute and chronic (primarily inflammatory and caused by allergens) diseases of the respiratory tract of various etiologies (bronchitis, allergic bronchitis, bronchial asthma, h-

COPD), as well as diseases of the arthritic type (rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions).

The pharmaceutical preparations proposed in the invention are most suitable, in addition, for use among those patients who suffer from the above-mentioned diseases and who have problems with taking pharmaceutical preparations intended for oral use, for example, in bedridden patients, in patients who are "in the department intensive care, in patients with impaired swallowing function and in children. The present invention further relates to a method of treating mammals, including humans, suffering from one of the above-mentioned diseases. This method differs in that a therapeutically effective and pharmacologically acceptable amount of a pharmaceutical active substance selected from the group of compounds that includes roflumilast, roflumilast salts,

M-oxide of roflumilast and its salts, and which is introduced into the body as part of the pharmaceutical preparation proposed in the invention for local use. Diseases for the treatment of which it is preferable to use the method proposed in the invention are acute and chronic (primarily inflammatory and caused by allergens) diseases of the respiratory tract of various etiologies (bronchitis, allergic bronchitis, bronchial asthma, "with COPD), as well as diseases of the arthritic type ( rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions). The method proposed in the invention differs in that the introduction of the active substance into the body consists in its epidermal application, that is, in applying the pharmaceutical preparations proposed in the invention for local use to the skin or mucous membranes.

The dosage forms proposed in the invention contain a pharmaceutical active ingredient in a dose that is usually used for the treatment of one or another specific disease. The dosage of the active substance corresponds to the order of values traditionally accepted for ROE inhibitors, while the daily dose can be administered into the body in one or several single doses. Traditional dosages of the active substance are described, for example, in (MO

GF) 95/01338Y. The daily dose of the active substance in systemic therapy (when administered orally) is normal

F is from 0.001 to Zmg per kilogram of body weight. The preferred dosage forms proposed in the invention for local use contain roflumilast in a single dose, which is from 0.005 to 5 mg, preferably from 0.01 to 2.5 mg, most preferably from 0.1 to 0.5 mg. As an example of the pharmaceutical preparations proposed in the invention, dosage forms can be named, each of which contains roflumilast in a single dose, which is

O,O1mg, O,mg, 0.125mg, 0.25mg or 0.5mg.

Claims (8)

The formula of the invention b5 1. A pharmaceutical preparation for local use, which contains a pharmaceutical active ingredient, which is a compound selected from the group consisting of roflumilast, roflumilast salts and the M-oxide of the pyridine residue of roflumilast or its salts, together with one or more pharmaceutical carriers and/or excipients suitable for local use, and which is a semi-solid pharmaceutical preparation that contains polyethylene glycol as one of the excipients. 2. A pharmaceutical preparation for local use according to claim 1, in which roflumilast is a compound of the formula gyno 70 and Ky dz o 75 in which: K1 means a difluoromethoxy group, K2 means a cyclopropylmethoxy group and KZ means 3,5-dichloropyrid-4-yl. 3. Pharmaceutical preparation for local use according to claim 1, which is presented in the form of a semi-solid dosage form selected from the group that includes ointments, such as, for example, ointment-solution and suspension ointment, creams, gels and pastes. 4. Pharmaceutical preparation for local use according to claim 1, in which polyethylene glycol is polyethylene glycol 400. 5. Use of an active ingredient selected from the group including roflumilast, roflumilast salts, or roflumilast C-oxide or its salts, for the preparation of a pharmaceutical preparation for local cutaneous use according to claim 1, intended for the systemic treatment of diseases selected from the group includes (o) acute and chronic, primarily inflammatory and caused by allergens, diseases of the respiratory tract of various etiologies, in particular bronchitis, allergic bronchitis, bronchial asthma and chronic obstructive pulmonary disease and diseases of the arthritic type, in particular rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and o 30. Other arthritic conditions. 6. Application according to claim 5, in which the pharmaceutical preparation for local use is a transdermal therapeutic system (TT). b 7. Application according to claim 5, in which the transdermal therapeutic system is a system with a controlled release of a medicinal substance due to penetration through a membrane, or a system with a controlled release of a medicinal substance due to diffusion through a matrix, or a system with controlled release using microreservoirs release of medicinal substance. 8. Use of a substance selected from roflumilast, one of the salts of roflumilast or the M-oxide of roflumilast, or one of its salts for the preparation of a pharmaceutical preparation for topical application according to claim 1, which is intended for the treatment of dermatoses selected from the group that includes psoriasis « 20 (scaly lichen), toxic and allergic contact eczema, atopic dermatitis, seborrheic eczema, lichen simplex, solar erythema, itching in the genital area and anus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and large pyodermas , endogenous and exogenous acne, pink acne and other proliferative, inflammatory and allergic skin diseases. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated circuit microcircuits", 2008, M 4, 25.10.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. - (Se) - 50 s2 F) ko 60 b5